Bárbara Angel

Vitamin D receptor polymorphism and susceptibility to type 1 diabetes in chilean subjects: A case-parent study

Several reports have found a relation between polymorphisms of the vitamin D receptor gene (VDR) and the development of type 1 diabetes. We have examined the association of three VDR polymorphism with type 1 diabetes in 59 Chilean case-parents trios. Genotyping for Bsm1, Apa1 and Taq1 polymorphism were performed. Transmission/disequiibrium tests were used to assess gene-disease associations through the evaluation of allelic transmission to affected offspring. Non-significant increased transmissions of B allele (probability of transmission=52.5, p=0.69), A allele (probability of transmission=58.4, p=0.17) and T allele (probability of transmission=52.0, p=0.77) were estimated in Bsm1, Apa1 and Taq1 sites, respectively. Haplotype-based analyses showed non-significant preferential transmissions (global p=0.52). The present study does not support the hypothesis of a significant contribution of VDR alleles in the etiology of type 1 diabetes of Chilean cases.

Efecto sobre la salud de las desigualdades socioeconómicas en el adulto mayor. Resultados basales del estudio expectativa de vida saludable y discapacidad relacionada con la obesidad (Alexandros)

Background: The rapid increase in life expectancy in Chile, with obesity as the main nutritional problem in all age groups, makes it necessary to ask whether the years gained are healthy. Aim: To study the trajectories of disability associated with obesity in Chilean elderly groups from different socio-economic and demographic backgrounds. Material and Methods: Longitudinal study of 3 cohorts of older adults from Santiago: the SABE cohort including 1235 people born before 1940; the Alexandros cohort including 950 people born between 1940 and 1948 from Primary Health Care centers and the ISAPRES cohort of 266 people from private health insurance registries (ISAPRES) born before 1947. An interview yielded socio demographic data and history of diseases. Anthropometric measurements and hand dynamometry were performed. Cognitive status was assessed by the mini mental state examination, depressive symptoms through the geriatric depression socore-5 and functional limitations through self-reporting of basic (ADL), instrumental (IADL) and advanced daily living (AADL) activities. Results: We report here baseline results from ISAPRES and SABE cohorts. Important social and gender differentials were observed. After adjustment by age and gender, a significant lower frequency of limitations in ADL (odds ratio (OR) = 0.17; 95% confidence intervals (CI): 0.079-0.343), IADL (OR = 0.27; 95%CI: 0.159-0.452), and AADL (OR = 0.42; 95%CI: 0.298-0.599) persisted in the ISAPRE cohort, compared to the SABE cohort. Obesity was associated with functional limitations only in AADL (OR = 1.65; 95%CI: 1.18-2.31) and hand dynamometry was associated with lower functional limitation in ADL, IADL and AADL. Conclusions: This study demonstrates profound socio-economic and gender inequalities in older people, thus showing that the years of healthy life gained are not the same for the whole society.BACKGROUND The rapid increase in life expectancy in Chile, with obesity as the main nutritional problem in all age groups, makes it necessary to ask whether the years gained are healthy. AIM To study the trajectories of disability associated with obesity in Chilean elderly groups from different socio-economic and demographic backgrounds. MATERIAL AND METHODS Longitudinal study of 3 cohorts of older adults from Santiago: the SABE cohort including 1235 people born before 1940; the Alexandros cohort including 950 people born between 1940 and 1948 from Primary Health Care centers and the ISAPRES cohort of 266 people from private health insurance registries (ISAPRES) born before 1947. An interview yielded socio demographic data and history of diseases. Anthropometric measurements and hand dynamometry were performed. Cognitive status was assessed by the Mini Mental State Examination, depressive symptoms through the geriatric depression score-5 and functional limitations through self-reporting of basic (ADL), instrumental (IADL) and advanced daily living (AADL) activities. RESULTS We report here baseline results from ISAPRES and SABE cohorts. Important social and gender differentials were observed. After adjustment by age and gender, a significant lower frequency of limitations in ADL (odds ratio (OR) = 0.17; 95% confidence intervals (CI): 0.079-0.343), IADL (OR = 0.27; 95%CI: 0.159-0.452), and AADL (OR = 0.42; 95%CI: 0.298-0.599) persisted in the ISAPRE cohort, compared to the SABE cohort. Obesity was associated with functional limitations only in AADL (OR = 1.65; 95%CI: 1.18-2.31) and hand dynamometry was associated with lower functional limitation in ADL, IADL and AADL. CONCLUSIONS This study demonstrates profound socio-economic and gender inequalities in older people, thus showing that the years of healthy life gained are not the same for the whole society.

Relationship between Nocturnal Growth Hormone Concentrations, Serum IGF-I/IGFBP-3 Levels, Insulin Sensitivity and GH Receptor Allelic Variant in Small for Gestational Age Children

Growth hormone may help to increase final height in patients with short stature, but its efficacy is variable. It has been recently reported that the isoform of the GH receptor (GHR) that lacks exon 3 (d3-GHR) is associated with a greater growth response to GH therapy. We hypothesized that nocturnal growth hormone concentrations, basal IGF-I and IGFBP-3 levels, and insulin sensitivity might show variations among individuals depending on their GHR allelic variant. To test this hypothesis, we studied 38 prepubertal LBW children with nocturnal GH concentrations, IGF-I and IGFBP-3 levels and insulin sensitivity during OGTT and Insulin test. The GHR allelic variant was analyzed through multiplex PCR analysis in DNA from peripheral leukocytes. Characteristics of the overnight GH secretion [(mean GH: 6.8 ± 0.6 vs. 6.2 ± 0.5 ng/ml), (AUC: 3,227 ± 280 vs. 2,908 ± 212 ng/ml·min), (peak number: 4.4 ± 0.3 vs. 4.4 ± 0.2), (amplitude: 12 ± 1.1 vs. 10.8 ± 1.1 ng/ml)] did not differ between groups (f1/f1 vs. f1/d3 plus d3/d3). In addition, we did not observe any significant differences in serum IGF-I SDS (–0.49 ± 0.26 vs. –0.40 ± 0.35) or IGFBP-3 SDS (–1.21 ± 0.24 vs. –0.89 ± 0.21) nor in insulin sensitivity (WIBSI: 12 ± 1.2 vs. 10.8 ± 1.1) in LBW children with full length GHR compared to children carrying at least one GHRd3 allele. The distribution of the f1/f1 allelic variant and fi/d3 or d3/d3 was similar in the LBW children with or without catch-up growth. These results suggest that the GHR allelic variant does not play a significant role in the regulation of GH-IGF-I/BP3 axis or in insulin sensitivity in prepubertal LBW children.

Lack of association between the fatty acid binding protein 2 (FABP2) polymorphism with obesity and insulin resistance in two aboriginal populations from Chile

The aim of this study was to assess the frequency of fatty acid binding protein 2 (FABP2) Ala54Thr genetic polymorphism and to evaluate its association with obesity and insulin resistance in Chilean aboriginal populations. A sample of 96 urban Aymara and 111 urban Mapuche subjects aged 20–80 years were recruited for this cross-sectional study. Glucose, insulin and lipid profile were measured in fasting plasma samples. Insulin resistance was estimated through the HOMA-IR model. FABP2 Ala54Thr genotypes were determined by PCR followed by RFLP analysis. The allele frequency of Thr54 variant was estimated as 18.2% in Aymara subjects, which is one of the lowest reported to date. The corresponding frequency in Mapuche subjects was 31.9% (p<0.002). Regarding genotype–phenotype associations, no significant differences were found in any of the anthropometric or metabolic variables according to Ala54Thr genotypes. After adjustment by BMI and metabolic variables through a logistic regression analysis, the association of the FABP2 polymorphism with ethnic group persisted (Mapuche group: OR=2.37, 95% CI 1.319–4.277, p=0.004) It is unlikely that Ala54Thr polymorphism of the FABP2 gene plays a relevant role in obesity and insulin resistance in Chilean ethnic groups.

Asociación del polimorfismo Fok I del gen del receptor de vitamina D (VDR) con concentraciones plasmáticas del factor transformador de crecimiento ß1 e interferón gamma en la diabetes mellitus tipo 1

Fundamento y objetivo: Analizar el polimorfismo Fok I del gen del receptor de vitamina D (VDR) y su relacion con la susceptibilidad a desarrollar diabetes tipo 1. Se realizo un estudio de casos y controles y se relacionaron los genotipos del VDR con las concentraciones circulantes de 25(OH)-vitamina D y las concentraciones sericas de factor transformador de crecimiento s1 (TGF-s1) e interferon gamma (INF-*). Pacientes y metodo: Se analizaron 151 casos de diabetes tipo 1 y 182 controles sanos no relacionados. Se amplifico el exon 2 del gen VDR mediante reaccion en cadena de la polimerasa. Los genotipos se obtuvieron mediante analisis de fragmentos de restriccion. La concentracion de 25(OH) vitamina D se determino por radioinmunoanalisis y las de las citocinas TGF-s1 e INF-*, por enzimoinmunoanalisis. Resultados: La distribucion del polimorfismo Fok I no mostro diferencias entre casos y controles. El grupo de ninos diabeticos mostro valores mas altos de TGF-s1 (mediana, 282,6 pg/ml; intervalos, 131,8-3.031,4) que los ninos controles (mediana, 232,2 pg/ml; intervalos, 135,7-506,5) (p < 0,0038). Tambien se observaron valores aumentados de INF-* (mediana, 121,1 pg/ml; intervalos, 5,3-228,8) en los casos comparados con los controles (mediana, 89,6 pg/ ml; intervalos, 10,9-117,2) (p < 0,0004). Los pacientes diabeticos portadores del genotipo ff mostraron concentraciones de 25(OH) vitamina D menores que los portadores del alelo F: media (desviacion estandar) de 23,1 (5,9) frente a 27,9 (10,3) ng/ml (p < 0,03). De forma similar, los diabeticos portadores del genotipo ff mostraron valores aumentados de TGF-s1 al compararlos con los genotipos portadores del alelo F (298,5 frente a 276,6 pg/ml; p < 0,05). Conclusiones: El polimorfismo Fok I del VDR podria tener un papel marginal en la alteracion inmunologica que se desarrolla en la diabetes tipo 1 a traves de una posible modulacion de la vitamina D.

PREDICCIÓN DE LA MASA MUSCULAR APENDICULAR ESQUELÉTICA BASADO EN MEDICIONES ANTROPOMÉTRICAS EN ADULTOS MAYORES CHILENOS

OBJECTIVES To develop a predictive model of appendicular skeletal muscle mass (ASM) based on anthropometric measurements in elderly from Santiago, Chile. METHODS 616 community dwelling, non-disabled subjects ≥ 60 years (mean 69.9 ± 5.2 years) living in Santiago, 64.6% female, participating in ALEXANDROS study. Anthropometric measurements, handgrip strength, mobility tests and DEXA were performed. Step by step linear regression models were used to associate ASM from DEXA with anthropometric variables, age and sex. The sample was divided at random into two to obtain prediction equations for both subsamples, which were mutually validated by double cross-validation. The high correlation between the values of observed and predicted MMAE in both sub-samples and the low degree of shrinkage allowed developing the final prediction equation with the total sample. RESULTS The cross-validity coefficient between prediction models from the subsamples (0.941 and 0.9409) and the shrinkage (0.004 and 0.006) were similar in both equations. The final prediction model obtained from the total sample was: ASM (kg) = 0.107(weight in kg) + 0.251( knee height in cm) + 0.197 (Calf Circumference in cm) +0.047 (dynamometry in kg) - 0.034 (Hip Circumference in cm) + 3.417 (Man) - 0.020 (age years) - 7.646 (R2 = 0.89). The mean ASM obtained by the prediction equation and the DEXA measurement were similar (16.8 ± 4.0 vs 16.9 ± 3.7) and highly concordant according Bland and Altman (95% CI: -2.6 -2.7) and Lin (concordance correlation coefficient = 0.94) methods. CONCLUSIONS We obtained a low cost anthropometric equation to determine the appendicular skeletal muscle mass useful for the screening of sarcopenia in older adults.

Déficit de vitamina B12 asociado con altas dosis de metformina en adultos mayores diabéticos

INTRODUCTION The aim of the study was to estimate if B12 deficiency is associated with the use of metformin in the elderly diabetics. METHODS Case-control study in diabetic OP. Cases (n = 137) were defined as elderly with B12 < 221 pmol/L and controls (n = 279) elderly with B12 > 221 pmol/L. Four categories of metformin use were defined: non-users, ≤850 mg/day, > 850 and < 2,550 mg/day and ≥2,550 mg/day. Metformin ≥2,550 mg/day was high doses considered. The crude OR for B12 deficiency and consumption of Metformin were calculated. Logistic regression models were developed to explore the association between B12 deficiency and metformin dose. The research protocol was approved by the Ethics Committee of INTA. RESULTS The age of cases and controls was (70.2 years vs 68.6 years (p < 0.05). The 62% were women in cases vs 74.9% in controls (p < 0.05). The 73% of cases and 76% of controls used metformin (p < 0.05) the average consumption of metformin was de 1,954.3 mg/day (SD: 1,063.2) in cases and 1,696.6 mg/day (SD: 1,074.4) in controls (p < 0.05). The use of 2,550 mg/day was observed in 29.2% of cases and 19.3% for controls (p < 0.05). It was observed that OP who consumed high doses of metformin had 1.9 times the risk of B12 deficiency (OR: 1.9; 95%CI: 1,08- 3,30). CONCLUSION These results show a strong association between high doses of metformin and low levels of vitamin B12 in diabetic elderly. This project was funded by FONIS SA11I2092.

Mini Nutritional Assessment short-form: Validation in five Latin American cities. SABE study

ObjectivesTo validate the short-form of the MNA (MNA-SF) and the cut-off point of 31 cm for calf circumference (CC) in older people in Latin America.MethodsA cross-sectional study was conducted with 5,722 community-dwelling older subjects (range: 60-102 years) in Latin America’s five main cities: Sao Paulo (Brazil), Santiago (Chile), Havana (Cuba), Mexico DF (Mexico) and Montevideo (Uruguay). All participants underwent an interview, which included anthropometric measurements, completing the MNA and obtaining socio-demographic, nutrition and health information. The short-form of the MNA consists of only six questions from the original 18. It has two versions: one using body mass index (BMI) and the second using CC as a surrogate. Cohen’s Kappa was calculated to assess the agreement between the MNA and the MNA-SF; diagnostic tests were performed, and Receiver-operating characteristic (ROC) curves were developed. Criterion-related validity was assessed in the Chilean sample.ResultsBoth version of the MNA-SF showed high sensitivity and specificity with the MNA, showing good accuracy (0.88), although higher values were estimated for malnutrition and risk of malnutrition in the total sample by sex. The cut-off point of 31 cm for CC showed high sensitivity (74.6-94.4%), specificity (72.6-100%) and good area under the ROC curve (0.87-0.95) when compared with BMI. There was good agreement between MNA and both version of MNA-SF for identifying persons with malnutrition or a risk of malnutrition in the five cities (Kappa coefficient: 0.6193-0.7852).ConclusionBoth versions of the MNA-SF are population-screening tools of easy and fast application, with good accuracy for assessing malnutrition and risk of malnutrition in Latin American older people.

Ala54Thr polymorphism of the fatty acid-binding protein 2 gene (intestinal-type FABP) is associated with changes in insulin sensitivity in SGA pubertal girls.

INTRODUCTION Associations between FABP2 Ala54Thr polymorphism and increased fasting insulin concentration, fasting fatty acid oxidation and reduced glucose uptake have been identified in several populations. The aim of this study was to evaluate the association of Ala54 Thr polymorphism of the FABP2 gene with insulin sensitivity in pubertal girls born small for gestational age (SGA). RESULTS The frequency of the Thr54 allele did not differ between AGA and SGA girls (0.52 vs 0.43). Girls born SGA positive for the Ala/Thr polymorphism were older at the beginning of puberty compared to girls born AGA with the Thr54 allele (p < 0.01). These girls had lower whole body insulin sensitivity index (WBISI) (4.1 +/- 1.7 vs 9.2+/-7.4, p < 0.05), higher leptin (17.3 +/- 5.9 vs 12.1 +/- 13.7, p < 0.02), insulin area under the curve (AUC) (64,272 +/- 9,209 vs 27,981 +/- 15,637, p < 0.001), proinsulin (17.3 +/- 5.4 vs 10.9 +/- 3.6, p < 0.01) and insulinogenic index (4.6 +/- 3.0 vs 2.9 +/- 5.9, p < 0.01). Conversely, girls born SGA positive for the Ala/Thr polymorphism were older at the beginning of puberty (ns) compared to girls born SGA positive for the Ala/Ala polymorphism. These girls had higher insulin AUC (64,272 +/- 9,209 vs 33,322 +/-7,533, p < 0.01), insulinogenic index (4.6 +/- 3.0 vs 2.5 +/- 3.6, p < 0.01) and lower WBISI (4.1 +/- 1.7 vs 6.3 +/- 1.8, p < 0.05). DISCUSSION Our results suggest that the Thr54 variant of the FABP2 gene could be associated with a synergic effect in the SGA group regarding higher leptin levels (p < 0.05), lower insulin sensitivity by WBISI (p < 0.05) and higher insulin secretion determined by higher insulinogenic index (p < 0.01), insulin AUC (p < 0.01) and beta-cell stress measured by higher proinsulin (p < 0.05). Our data suggest an involvement of genetic factors in the insulin resistance associated with reduced fetal growth and strengthen the hypothesis that this association could be the consequence of interactions between detrimental factors during fetal life and genetic susceptibility.

FokI polymorphism in vitamin D receptor gene: Differential expression of TNFα in peripheral mononuclear cells of type 2 diabetic subjects

Introduction FokI polymorphism has been associated with obesity and type 2 diabetes (T2D) in some populations. Objective To investigate the frequencies of a genetic polymorphism of Vitamin D receptor (FokI) in patients with T2D and control subjects and investigate the role of 1,25(OH)2D3 in the expression of pro-inflammatory markers in peripheral blood mononuclear cells (PBMCs). Methods The case–control study was conducted in 160 patients with T2D and 160 control subjects, men and women (30–74 years old). The genotype and allele frequency of FokI polymorphisms were determined in these subjects. Subsequently a subgroup of 40 subjects was included from which PBMCs were removed. In vitro, the culture medium was supplemented with two different concentrations of 1,25(OH)2D3(10− 8 M and 10− 10 M). The expression profiles of TNFα and mRNA were analysed by qPCR, and GAPDH and β-actin were used as housekeeping genes. Results The control subjects have an increased frequency of the FF genotype. In subjects with T2D, the ff genotype was associated with higher HOMA-IR values than individuals with genotype Ff (p = 0.021). In vitro study in PBMCs showed differential expression of TNFα mRNA by FokI genotype, with a lower expression of this marker of inflammation in FF genotype subjects at a concentration of 10− 8 M of 1,25(OH)2D3. Conclusion Our data suggest that VDR FokI polymorphism is associated with T2D, and the genotypes Ff and ff of this variant show a reduced response or resistance to the anti-inflammatory action of VitD, which could indicate a functional role of FokI polymorphism of VDR.